Substituted phenylalkanol derivatives

ABSTRACT

PHENYLALKANOL DERIVATIVES OF THE FORMULA   1-((-(CH2)N-CH(-O-R2)-CH2-)&gt;N-),2-R4,4-(R1-CH2-CH(-R3)-)   BENZENE   WHEREIN R1 IS OH, ALKOXY OF UP TO 6 CARBON ATOMS, CYCLOALKOXY OF UP TO 6 CARBON ATOMS, ARYLOXY OF 6-12 CARBON ATOMS, ARALKOXY OF 7-12 CARBON ATOMS, OR ACYLOXY OF UP TO 18, PREFERABLY UP TO 6, CARBON ATOMS; R2 IS H, ALKYL OF UP TO 6 CARBON ATOMS, CYCLOALKY OF UP TO 6 CARBON ATOMS, ARYL OF 6-12 CARBON ATOMS, ARALKYL OF 7-12 CARBON ATOMS, OR ACYL OF UP TO 18, PREFERABLY UP TO 6, CARBON ATOMS; R3 IS H OR CH3; R4 IS C1, BR OR CH3; AND N IS 2 OR 3; AND THE PHYSIOLOGICALLY ACCEPTABLE ACID ADDITION SALTS AND QUATERNARY AMMONIUM SALTS THEREOF; POSSESS USEFUL PHARMACOLOGICAL ACTIVITY, INCLUDING ANTIPHLOGISTIC. ANALGESIC AND ANTIPYRETIC EFFECTS.

United States Patent 3,770,748 SUBSTITUTED PHENYLALKANOL DERIVATIVESJoachim Borck, Johann Dahm, Jan Willem Hovy, Josef Kramer, and AlbrechtWild, Darmstadt, Germany, assignors to Merck Patent Gesellschaft mitbeschrankter Haftung, Darmstadt, Germany No Drawing. Filed Mar. 24,1972, Ser. No. 237,879 Claims priority, application Germany, Mar. 25,1971, P 21 14 420.7 Int. Cl. C07d 29/24 US. Cl. 260293.81 21 ClaimsABSTRACT OF THE DISCLOSURE Phenylalkanol derivatives of the formulamn-nQ-onm-omm wherein R is OH, alkoxy of up to 6 carbon atoms,cycloalkoxy of up to 6 carbon atoms, aryloxy of 612 carbon atoms,aralkoxy of 7-12 carbon atoms, or acyloxy of up to 18, preferably up to6, carbon atoms; R is H, alkyl of up to 6 carbon atoms, cycloalkyl of upto 6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 7-12 carbonatoms, or acyl of up to 18, preferably up to 6, carbon atoms; R is H orCH R is Cl, Br or CH and n is 2 or 3; and the physiologically acceptableacid addition salts and quaternary ammonium salts thereof; possessuseful pharmacological activity, including antiphlogistic, analgesic andantipyretic effects.

BACKGROUND OF THE INVENTION This invention relates to novel substitutedphenylalkanol derivatives, to processes for the preparation thereof,pharmaceutical compositions comprising them and methods of use thereof.

SUMMARY OF THE INVENTION The novel compounds of this invention arephenylalkanol derivatives of the general Formula I wherein R is OH,alkoxy of up to 6 carbon atoms, cycloalkoxy of up to 6 carbon atoms,aryloxy of 6-12 carbon atoms, aralkoxy of 7-12 carbon atoms, or acyloxyof up to 18, preferably up to 6 carbon atoms; R is H, alkyl of up to 6carbon atoms, cycloalkyl of up to 6 carbon atoms, aryl of 612 carbonatoms, aralkyl of 7-12 carbon atoms, or acyl of up to 18, preferably upto 6 carbon atoms, R, is H or CH R is Cl, Br or CH and n is 2 or 3; andthe physiologically acceptable acid addition salts and quaternaryammonium salts thereof, and mixtures thereof.

Compounds of Formula I and the physiologically acceptable acid additionand quaternary ammonium salts thereof, possess, with good compatibility,an excellent antiphlogistic effect, usually accompanied by analgesic andantipyretic effects. They also possess one or more of bacteriostatic,bactericidal, antiprotozoal, diuretic, bloodsugar-lowering, choleretic,cholesterol-level-lowering and radiation-protective activity. Thecompounds of Formula I and their physiologically acceptable salts canthus be employed as drugs as well as intermediates for the production ofother drugs.

3,770,748 Patented Nov. 6, 1973 DETAILED DISCUSSION Of the compounds ofthis invention of Formula I, the following are preferred:

IbR =acyloXy of up to 18 carbon atoms;

IdR =acyloxy of up to 18 carbon atoms and n is 3;

IfR =acyl of up to 18 carbon atoms;

Ih-R =acyl of up to 18 carbon atoms and n is 3;

ImR =acyloxy of up to 18 carbon atoms, R =H,

R3=CH3,

In-R =acyloxy and R is acyl, each of up to 18 carbon atoms, R =CH R =Cl;

Ip--R =acyloxy of up to 18 carbon atoms, R =H,

R3=CH3, R4=CL IqR =acyloxy and R is acyl, each of up to 18 carbon atoms,R =CH R =Cl, n=3;

including the pharmaceutically acceptable acid addition and quaternarysalts thereof, acyloxy and acyl in each instance preferably containingup to 6 carbon atoms, e.g., alkanoyloxy and alkanoyl.

In its process aspect, this invention relates to a process for thepreparation of substituted phenylalkanol derivatives of the generalFormula I which comprises any one of the following:

(a) a compound of the general Formula H RnOCH-CH2 wherein X, is a groupconvertible into a group of the formula CHR CH R (=Z is reacted with acompound which converts the group X into the group of Formula Z (b) acompound of the Formula HI wherein X is a group convertible into thegroup of the formula Ra (W1) is reacted with a compound which convertsthe group X into a group of Formula W R R R and R n, X and X in eachinstance having the values given above;

and/ or optionally a thus-obtained compound of Formula I is convertedinto another compound of Formula I; and/ or optionally a thus-obtainedcompound of Formula I is converted into the physiologically acceptableacid addition salts or quaternary ammonium compounds thereof, or isliberated from the acid addition salts thereof; and a thus-producedracemate or racemate mixture is separated into a pure racemate and/orenantiomer.

This invention also relates to pharmaceutical preparations comprising atleast one compound of the general Formula I in suitable unit dosageform, in admixture with at least'one solid, liquid or semiliquidauxiliary agent or vehicle, and optionally at least one further activecompound, preferably those containing 0.1400 mg. of a compound ofFormula I per unit dosage. This invention also relates to a method forobtaining antiphlogistic, analgesic and/or antipyretic effects in livingbeings, by the administration thereto of a composition of thisinvention.

In the above formulae, R in addition to a free OH group, can also be anetherified or esterified OH group. Examples of etherified OH groups arealkoxy, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec.-butoxy, isobutoxy, tert.-butoxy, amyloxy, isoamyloxy, hexyloxy andisohexyloxy; cycloalkoxy groups, e.g., cyclobutyloxy, cyclopentyloxy andcyclohexyloxy; heterocycloalkoxy, e.g., tetrahydrofuran-2-yloxy,tetrahydropyran- 2'-yloxy and 4-alkoxytetrahydropyran-4'-yloxy; aryloxy,e.g., phenoxy, p-tolyloxy, xylyloxy and naphthyloxy; and aral-koxy, e.g.benzyloxy, l-phenylethyloxy and 2-phenylethyloxy.

Examples of esterified OH groups are those esterified with a saturatedor unsaturated aliphatic, cycloaliphatic, aromatic, araliphatic, orheterocyclic, substituted or unsubstituted carboxylic acid or sulfonicacid. Preferred carboxylic acids are fatty acids, preferably alkanoicacids, of 1-18, particularly 1-6 carbon atoms, e.g., formic, acetic,propionic, butyric, isobutyric, valeric, isovaleric, caproic,isocaproic, enanthic, caprylic, capric, lauric, myristic, palmitic andstearic acid; and other carboxylic acids, e.g., pivalic acid,diethylacetic acid, oxalic acid, malonic acid, succinic acid, pimelicacid, acrylic acid, fumari acid, maleic acid, cyclohexanecarboxylicacid, benzoic acid, phenylacetic acid, phenylpropionic acid, gluconicacid, furan-Z-carboxylic acid, nicotinic acid and isonicotinic acid.

The OH groups can also be esterified with a sulfonic acid includingaliphatic and arylsulfonic acids, e.g., methanesulfonic acid,ethanedisulofnic acid, fi-hydroxyethanesulfonic acid, p-toluenesulfonicacid, p-bromobenzenesulfonic acid, naphthalene-monoand -disulfonicacids, or camphorsulfonic acid, or with an inorganic acid, preferablysulfuric acid or a phosphoric acid, e.g., orthophosphoric acid.

R in addition to H, can also be alkyl of up to 6 carbon atoms, e.g.,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl,n-pentyl, isopentyl, n-hexyl and isohexyl, or the acyl radical of anacid of up to 18, preferably up to 6 carbon atoms, e.g., an acid namedabove.

X is a group which can be converted into a group of Formula Z Examplesof such groups are those of the formula -CHR -A, wherein A is a groupwhich can be converted into a moiety of the formula -CH R by reactionwith a reducing agent. A can, for example, be an aldehyde group, in freeor functionally modified form, for example as an acetal, e.g., adialkylacetal group, preferably a dimethylor diethylacetal group; analkyleneacetal group, preferably an ethyleneacetal of1,2-propyleneacetal group; or a free or optionally a functionallymodified carboxyl group, preferably an alkoxycarbonyl group of up to 7carbon atoms, especially methoxycarbonyl, ethoxycarbonyl, orisopropoxycarbonyl, or an aralkoxy carbonyl group of up to 9 carbonatoms, especially benzyloxycarbonyl. It is also possible to employ acarboxylic acid halogenide, preferably a carboxylic acid chloride orbromide; a carboxylic acid anhydride group of up to 16 carbon atoms,preferably an acetoxycarbonyl group; a carboxylic acid azide or amidegroup; or a nitrile group.

X can, for example, also be one of the following groups: -C(=CH )-CH R(Z X can also be a group of the formula -CHR -CH Y wherein Y is Cl, Br,I, or a reactively modified OH group, e.g., an alkylsulfonyloxy group ofup to 4 carbon atoms, a methanesulfonyloxy or ethanesulfonyloxy group,or an arylsulfonyloxy group of up to 10 carbon atoms, preferablyp-tolylsulfonyloxy or a p-bromosulfonyloxy, or tetrahydropyranyloxy.

X, can also be an oxiran-Z-yl or a Z-methyl-oxiran-Z-yl group.

X is a group which can be converted into a group of the Formula W whichis preferably one of the followwherein U is Y(CH CH (OR )-CH YCH CH 0R(CH 7 0 H(CH2) n or (CEzZyCH-C Hr- Nz l (W3) wherein Y is C1 or Br;

RzO-CH CH3 CH=oH-(oH,) -N

Rio-OH CH2 4 (We) wherein m is n\2, i.e., 1 or O;

W TQ- R :C CH

5 2 iRt (Wu) acetate; an aprotic-dipolar solvent, e.g.,dimethylformamide, acetonitrile, dimethyl sulfoxide, tetramethylurea,tetrahydrothiophene 1,1-dioxide (sulfolane), propylene carbonate andhexamethylphosphoric triamide (hernpa); and mixtures of one or morethereof.

The starting compounds of Formula II A=optionally functionally modifiedcarboxyl) are preferably substituted 3-chloro-4-(3-hydroxypyrrolidino)-or -piperidino)-phenylacetic acids, substituted 2-[3-chloro-4-3-hydroxypyrrolidino -phenyl] or -hydroxypiperidino phenyl]-propionicacids and the esters thereof, preferably the alkyl, particularly themethyl and ethyl esters thereof, the acid halogenides, preferably thechlorides or bromides thereof, the anhydrides, optionally the mixedanhydrides thereof with other acids, acid azides, amides and nitriles.The starting compounds can also be the corresponding acids substitutedin the 3-position of the phenyl ring by Br or CH in place of C1, or theaboveindicated functional derivatives thereof.

The starting compounds of Formula II A=optionally functionally modifiedcarboxyl) are known, or they can be prepared in accordance withconventional processes described in the literature.

Thus, for example, the amides of Formula II are obtained by pouring thecorresponding carboxylic acid chlorides or bromides into an excessaqueous ammonia solution. These corresponding carboxylic acid chloridesand bromides can be obtained by treating the free acids with aninorganic acid chloride or bromide, e.g., SOClg, SO CI PCl PCl POCl PBror POBr If, in place of ammonia, a monoor dialkylamine is used, then thecorresponding monoor dialkylamides are obtained. The acid azides ofFormula II (X =-CHR CON can be obtained in accordance with conventionalmethods, e.g., by reacting the corresponding acid halogenides with NaNThe anhydrides of Formula II, i.e.,

wherein R is any desired organic residue, preferably, however, CH or((FHzh-IITQ-CHMY R20CH CH2 by reaction with an inorganic cyanide,preferably NaCN or KCN.

It is also possible to produce a nitrile of Formula II (X =CHR CN) bysplitting off Water from an amide of Formula II (X =CHR -OONH Aldehydesof the Formula II (X =-CHR CHO) are obtained, for example, by reactingan acetophenone of the Formula V (R =H):

with methoxymethyl triphenylphosphonium chloride and subsequent acidichydrolysis.

The allyl alcohols substituted in the 2-po-sition and/or the functionalderivatives thereof of Formula II (X =Z are obtained, for example, byreacting an a-alkoxyacetophenone of Formula V (Rq=OR3; R =alkoxy of upto 6 carbon atoms, cycloalkoxy of up to 6 carbon atoms, aryloxy of 6l2carbon atoms, aralkoxy of 7-12 carbon atoms, or acyloxy of up to 18,preferably up to 6 carbon atoms) with triphenylmethylphosphonium bromideand phenyl-lithium.

The vinyl ethers and/or vinyl esters of Formula II (X =Z or Z areproduced, for example, from aldehydes of Formula II (X =--CHR CHO) byheating in a mixture of an acid anhydride and an alkali salt of the sameacid. Preferably, the enol acetates are employed which are obtained fromthe aldehydes of Formula II by heating with acetic anhydride/sodiumacetate.

The styrene oxides II (X =oxiran-2-yl or Z-methyloxiran-Z-yl group) areproduced from the corresponding styrenes in accordance with conventionalmethods, for example by treatment with trifiuoroperacetic acid orperbenzoic acid.

Compounds of the Formula III (X =W can be produced in accordance withconventional processes by reacting compounds of the Formula VICH2OH(OHz)n-Y o (VIIb) with a compound of Formula VIII (R =RHzNQCHRsCHzR:

The diazonium salts of Formula III (X =W are obtained, for example, inaccordance with conventional methods, e.g., by reacting a compound ofFormula IX (ihN with a 3-hydroxypiperidine or 3-hydroxypyrrolidine, orthe Oalkyl or Oacyl derivatives thereof; reduction of the nitro group,preferably with a base metal in a mineral-acidic solution, for examplewith Fe in dilute HCl, by catalytic hydrogenation, or reduction in analkaline medium, e.g., with Zn dust in aqueous NaOH, as well assubsequent diazotization at temperatures of between 20 C. and +5 0.,preferably at 0 C., in a hydrochloric or hydrobromic aqueous solution,by adding the stoichiometric amount of an inorganic nitrite, preferablyNaNO or 'KNO However, using one of the customary organic solvents,diazotization can also be achieved by the addition of an organicnitrite, such as n-butyl nitrite, n-amyl nitrite, o-r isoamyl nitrite,preferably in the presence of HCl or HBr.

Compounds of Formula III (X =W are obtained, for example, from the2-(4-aminophenyl)ethanols or propanols of Formula VIII (R =H) byreaction with compounds of Formula VI, VIIa or VIIb.

Compounds of Formula III (X =W are obtained, for example, in aconventional manner from compounds of Formula X.

R4 (X) by bromination, preferably with a bromoimide, e.g., N-bromosuccinimide, in one of the customary solvents at temperatures ofbetween 20 and C., preferably at the boiling temperature of the solvent,optionally under simultaneous irradiation, preferably with short-wavelight, and subsequent solvolysis. Depending on the solvolyzing agentemployed, alcohols of Formula III (X =W R =H) or esters of Formula III(X =W R =acyl) are obtained.

Starting compounds of Formula III (X =W R =O) can be obtained, forexample, from compounds of Formula IX by reaction with 3-piperidoneor3-pyrrolidoneethylene ketal, followed by reduction of the nitro group,diazotization, and exchange of the diazonium group against chlorine orbromine under simultaneous saponification of the ketal group. When Rrepresents, for example, (H, Br), the corresponding compounds of FormulaIII are obtained by the bromination of compounds of Formula X followedby hydrogenation.

The compounds of Formula I are obtained from the compounds of Formula II(X =CHR -A) by treatment with a reducing, preferably hydrogen-evolvingagent, e.g., a complex metal hydride.

As reducing agents, catalytically activated hydrogen, hydrogen in thenascent state and chemical reducing agents can also be employed.

For catalytic hydrogenations, suitable catalysts are, for example, noblemetal, nickel and cobalt catalysts, for the reduction of carboxylic acidderivatives, mixed catalysts e.g., copper chromium oxide can also beemployed. The noble metal catalysts can be employed on supports, e.g.,platinum on carbon, palladium on calcium carbonate or strontiumcarbonate, as oxide catalysts, e.g., platinum oxide, or as finelydivided metal catalysts. Nickel and cobalt catalysts are suitably usedas Raney metals nickel on kieselguhr or pumice as the support can alsobe employed. The hydrogenation can be effected at room temperature andnormal pressure or also at an elevated temperature and/or an elevatedpressure. Preferably, the reaction is conducted under pressures ofbetween 1 and 100 atmospheres, occasionally, as in the hydrogenation ofesters with, for example Co(II) acetate, also under higher pressures,and at temperatures of between 80 C. and 200 C., especially between roomtemperature and +l C. The reaction is suitably effected in the presenceof one of the usual solvents. For purposes of the hydrogenation, thefree compounds or the corresponding salts can be utilized, e.g., thehydrochlorides or sodium salts.

In the hydrogenation of multiple bonds, the reaction is preferablyconducted under normal pressure and by terminating the hydrogenationafter absorption of the stoichiometric amount of hydrogen. Basically, itis possible to hydrogenate at an acidic, neutral or basic pH.

Another generally suitable reduction method is the reaction with nascenthydrogen. The latter can be produced, for example, by treating a metalwith an acid or base, e.g., a mixture of zinc and acid or alkalinesolution, iron and hydrochloric acid or acetic acid, or tin andhydrochloric acid. Furthermore, it is suitable to use sodium or anotheralkali metal in an alcohol, e.g., ethanol, isopropanol, butanol, amylalcohol, isoamyl alcohol or phenyl. In the reduction of carboxylic acidderivatives, the method of Bouveault-Blanc can be employed, preferablyat the boiling temperature of the alcohols used. Furthermore, analuminum-nickel alloy can be utilized in an alkaline-aqueous solution,optionally with the addition of ethanol. Sodium amalgam or aluminumamalgam in an aqueous-alcoholic or aqueous solution is also suitable forproducing nascent hydrogen. The reaction can also be effected in aheterogeneous phase, wherein suitably an aqueous phase and a benzene ortoluene phase are used. The reaction temperatures employed range betweenroom temperature and the boiling point of the solvent used.

When a complex metal hydride is utilized as the reducing agent, e.g.,LiAlH NaAlH (OCH CH OCH or NaBH optionally with the addition of acatalyst, e.g., BF AlCl or LiBr, the process is advantageously conductedin the presence of one of the usual solvents, preferably in an ether,e.g., diethyl ether, tetrahydrofuran or dioxane. The reactions areadvantageously conducted between 80 C. and the boiling point of thesolvent. The decomposition of the thus-formed metal complexes can bedone in the usual manner, e.g., with moist ether or an aqueous ammoniumchloride solution. A particularly preferred reducing agent is NaAlH (OCHCH OCI-I This compound can be employed for the reduction of aldehydes,carboxylic acids, carboxylic acid esters, anhydrides and halogenides ofFormula H (X =CHR -A) to compounds of Formula I.

Aldehydes of Formula II (X =CHR CHO) can also be reduced by theMeerwein-Ponndorf reaction, using aluminum alcoholates, preferablyaluminum isopropylate or ethylate, in, for example, benzene or tolueneat temperatures of between room temperature and the boiling point of thesolvent.

Nitriles of Formula II (X =CHR CN) can be converted into the alcohols ofFormula I, for example, by treatment with hydrogen in the presence ofRaney nickel 8 and a cation exchanger in an aqueous medium. Amides ofFormula H (X =-CHR CONH can also be split reductively to the alcohols ofFormula I by electrolysis in an aqueous-methanolic solution in thepresence of tetramethylammonium chloride.

A compound of Formula II (X =Z Z or Z can likewise be converted into acompound of Formula I by treatment with reducing agents, preferablyagents evolving hydrogen, e.g., sodium amalgam or catalyticallyactivated hydrogen.

When starting with an epoxide of Formula II (X=oxiran-Z-yl or2-methyloxiran-2-yl), compounds of Formula I are obtained, for example,by treatment with LiAlI-L, in the presence of AlCl or with BH BFpreferably in tetrahydrofuran at 0 C.

Compounds of Formula I are also obtained by reacting a halogen compoundor a sulfonic acid ester of Formula II (X =-CHR -CH Y) with asolvolyzing agent, e.g., an alcohol, an acid, or H O, preferably in thepresence of an acidic or basic catalyst, or with a metallic salt or ametallic alcoholate. Thus, alcohols of Formula I are obtained, forexample, by saponifying a halogen compound of Formula II (X =--CHR CH-Hal; Hal=Cl, Br, I) in an aqueous or aqueous-alcoholic solution orsuspension, optionally with the addition of a solubilizer, such as analcohol, glycol or polyglycol ether.

As the saponifying agent, bases or basic salts are generally employed,preferably alkalines, e.g., NaOH or KOH. It is also possible to useslurries of Ca( OH) Pb(OH) or AgOH. The saponification is ordinarilyconducted at an elevated temperature, for example at the boilingtemperature of the solvent. A halogenide of Formula II (X =CHR CH l-Ial)can, however, also be reacted in a non-aqueous medium, by agitating aboiling solution thereof in a usual solvent, with the exclusion ofwater, with suspended AgOH or Pb(OH) Esters of Formula I (R =OR R =H)are produced by the Williamson synthesis by reacting compounds ofFormula II (X =CHR CH OM; M: an equivalent of a metallic atom,preferably Na or K) with a compound of Formula XI wherein R is alkyl ofup to 6 carbon atoms, cycloalkyl of up to 6 carbon atoms, aryl of 612carbon atoms or aralkyl of 7l2 carbon atoms.

To obtain uniform products, the OH group in the heterocyclic ring isusually first masked, and the masking group is then split ofl after thereaction. Advantageously, the sodium alcoholate is produced by adding asolution of the alcohol of Formula I (R =OH) in a usual solvent dropwiseto a finely distributed suspension of the stoichiometric amount of Na inan inert solvent, preferably toluene or xylene. When the less reactivechlorides or bromides of Formula XI (Y=Cl or Br) are utilized, a smallamount of KI can be added. The reaction mixture is then refluxed untilit becomes neutral. Phenyl ethers are obtained by mixing the alcoholicalkali alcoholate solution with an equivalent of the respective phenol,and then continuing the procedure as described for the alkyl ethers.Additionally, suitable solvents for the production of the phenyl ethersare water or aqueous alcohols. It is also possible to react alkalialcoholates or phenolates of the formula R OM with halogen compounds ofFormula II If a suspension is used, especially suitable solvents areinert solvents, e.g., ether, tetrahydrofuran, acetone and benzene.According to this method it is, of course, also possible to prepare thediethers of Formula I by reacting starting compounds of Formula II (X-=-CHR CH OM; R =R with compounds of Formula XI.

Analogously, esters of Formula I (R =OAcyl; R =H) are produced byrefluxing compounds of Formula II (X =CHR --CH Y) in an aqueous,aqueous-alcoholic or alcoholic solution with the alkali salts of thecarboxylic acids to be esterified. Addition of triethylamine acceleratesthe reaction. When it is desired to obtain acetates of Formula I (R=OCOCH R =H), a preferred method is refluxing the halogenides orsulfonic acid esters of Formula II (X =CHR -CH Y) with a solution ofanhydrous sodium acetate in glacial acetic acid. To produce esters ofFormula I it is also possible to react halogen compounds of Formula II(X =CHR CH Hal) in one of the usual inert solvents with a silver salt ofthe corresponding acid. In all these reactions, to obtain uniformproducts, the OH group in the heterocycle generally is first masked andthe masking group is then split olf after the reaction.

The thus-obtained compounds of Formula I can also be converted intoother compounds of Formula I, for example, by esterifying the alcoholsof Formula I directly with excess acid, optionally in the presence ofone of the usual solvents, preferably a hydrocarbon, such as benzene ortoluene, to the corresponding diesters of Formula I (R =OAcyl; R =Acyl)with excess acid, optionally in the presence of one of the usualsolvents and/ or a sulfonic acid, such as p-toluenesulfonic acid, intoanother diester of Formula I.

Compounds of Formula I can be produced from starting materials ofFormula II wherein X is an oxiran-Z-yl or 2-methyloxiran-2-yl group, bytreatment with a hydrogen-evolving agent, preferably a hydride, e.g., BH or LiAlI-I in the presence of a Lewis acid, e.g., BF or AlCl Thereaction is carried out in one of the usual solvents, preferably anether, e.g., diethyl ether or tetrahydrofuran, at temperatures ofbetween -20 C. and +30 C., preferably between 5 C. and +5 C.

Starting with a compound of Formula III (X =W compounds of Formula I areobtained in accordance with conventional methods, by reacting with acyclizing agent, preferably by heating in an aqueous solution orsuspension, optionally in the presence of an acidic or basic catalyst,or in one of the usual organic solvents, preferably in an organic acid,e.g., formic acid, acetic acid or propionic acid, especially in thepresence of an acidic catalyst, e.g., HCl.

A particularly preferred and advantageous method is to produce acompound of Formula III (X =W and without isolating it, optionally withthe addition of a suitable catalyst, cyclize it directly to a compoundof Formula I. Depending on which starting materials are employed, theprocess is conducted at low temperatures, e.g., room temperature, or atelevated temperatures, preferably at the boiling temperature of thesolvent employed. In some cases, it may be necessary to conduct thereaction under pressure (up to 200 atmospheres) and/or at an elevatedtemperature (up to 300 C.). A catalyst, e.g., a base, such as NaOH, KOHor sodium or potassium carbonate can be used but is not absolutelynecessary.

Compounds of Formula I are also obtained by exchanging, in the diazoniumcompounds of Formula III the diazonium group for a C1 or Br atomaccording to methods described in the literature. The exchange forchlorine is preferably effected in an aqueous solution in the presenceof Cu Cl by the Sandmeyer method. The exchange for bromine can beconducted, for example, in an aqueous solution in the presence of Cu Braccording to Sandmeyer, or by reaction with bromine to form thediazonium perbromide, and subsequent refluxing in a suitable solvent,e.g., water or a lower alcohol. However, the diazonium bromides can alsobe converted into the diazonium mercury bromides with HgBr and these canbe thermally dissociated to the desired bromine compounds.

The R; group can be introduced into compounds of Formula III (X =W inaccordance with methods described in the literature, by directsubstitution, preferably by treatment with a chlorinating or brominatingagent.

Chlorination is effected, for example, by the direct reaction withelemental chlorine in an inert solvent, e.g., water, CCl acetic acid,without or with the addition of specific catalysts, e.g., FeCl AlCl SbClor SnCl preferably between 10 C. and 100 C., by reaction, in a stronglyhydrochloric solution, with H 0 or with NaClO- wherein chlorination isaccomplished with nascent chlorine by reaction with SO Cl in an inertsolvent, e.g., chlorobenzene, in the presence of a radical-formingcatalyst, e.g., a peroxide, at preferably l80 C.; by reaction with NO Clor NOCl in CS 'or hexane. Bromination can be achieved, for example, in aparticularly simple manner by direct reaction with elemental bromine inan inert solvent, e.g., CS acetic acid, or CCl especially with theaddition of a catalyst which act as bromine transfer agents, e.g., ironfilings, AlCl AlBr FeCl iodine or pyridine, preferably between 30 C. andC.; by reaction with hypobromous acid, an acyl hypobromite, N-bromoimide, e.g., N-bromosuccinimide, N-bromophthalimide or otherbromine-yielding agent, e.g., 1,3-dibromo- 5,5-dimethylhydantoin, in aninert solvent, e.g., nitrobenzone or CS preferably at l0 C. to C.; or byreaction with NOBr or NO Br in CS or cyclohexane.

Compounds of Formula I are obtained from the compounds of Formula III (X=W by treatment with a reducing, preferably hydrogen-yielding, agent.Thus, hydrogenation of the double bond in the heterocyclic ring can beconducted in accordance with one of the abovedescribed methods.

"Ethers of Formula I (R =OH; R =R can be produced by reacting compoundsof Formula III (X =W R =[H, 0M1) in accordance with the methods of theWilliamson synthesis with a compound of Formula XI. The above-describedreaction conditions can be employed.

Esters of Formula I (R =OH; R =Acyl) can also be prepared in accordancewith the above-described methods.

Compounds of Formula I can also be produced from compounds of FormulaIII (X =W R =[H, Y]) by treatemnt with a solvolyzing agent, e.g.,alcohols, acids, or with H O, preferably in the presence of an acidic orbasic catalyst, in accordance with known methods or by reaction with ametallic salt or metallic alcoholate.

An oxo compound of Formula III (X =W R =O) can be reduced in accordancewith conventional methods to the corresponding hydroxy compounds bytreatment with a reducing, preferably hydrogen-evolving agent,preferably a complex metal hydride. The reaction conditions must beselected so that the phenyl ring is not reduced, for example by usingNaBH in methanol, optionally in the presence of aluminum chloride orlithium bromide. The reaction is advantageously carried out in thepresence of one of the usual solvents, preferably lower alcohol, ether,tetrahydrofuran or ethylene glycol dimethyl ether. The reaction isadvantageously terminated by refluxing the reaction mixture. Thedecomposition of the thusformed metal complexes can be accomplished inthe usual way, for example with the use of an aqueous ammonium chloridesolution.

A variant of the aforedescribed methods resides in reacting a compound XX (X =CHR A, Z Z or Z X =W or W with R =O) with one of theabovementioned reducing agents. In this process, compounds of Formula II(X =CHR A, Z Z or Z or III (X =W or W with R =O), respectively, areformed as intermediates. These compounds, usually without being 11isolated, are further reacted to the compounds of Formula I.

It is also possible to react a compound of the formula Xz-X X2=W6 R5=[H,Y]) with one of the above-indicated sol'volyzing agents and, ratherthan isolating the thus-formed compounds of Formula II (X =CHR CH Y) orIII (X =W with R =[H, Y]), further react these compounds immediatelywith excess solvent to compounds of Formula I. These starting compoundsof the formula X -X can, however, also be reacted with two equivalentsof a metallic salt or metallic alcoholate, to produce compounds ofFormula I. It is particularly advantageous to convert a thus-obtainedcompound of Formula I (R =OH; R =H), in accordance with one of themethods described above, by alkylating or acylation into a diether ofFormula I (R =OR R =R or a diester of Formula I (R =OAcyl; R =Acyl). Insuch reactions, the corresponding monoethers or monoesters are usuallyobtained as intermediates, which are at once further alkylated oracylated, respectively.

A compound of Formula I can be converted into the associated acidaddition salt with the use of an acid. Suitable acids for such areaction are those yielding physiologically acceptable salts. Thus,organic and inorganic acids can be utilized, including aliphatic,alicyclic, araliphatic, aromatic and heterocyclic mono or polybasiccarboxylic or sulfonic acids, e.g., formic acid, acetic acid, propionicacid, pivalic acid, diethylacetic acid, oxalic acid, malonic acid,snccinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid,tartaric acid, malic acid, aminocarboxylic acids, sulfamic acid, benzoicacid, salicylic acid, phenylpropionic acid, citric acid, gluconic acid,ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid,ethanedisulfonic acid, ,B-hydroxyethanesulfonic acid, p-toluenesulfonicacid, naphthalenemonoand -disulfonic acids, sulfuric acid, nitric acid,hydrohalic acids, e.g., hydrochloric or hydrobromic acid, and/ orphosphoric acids, e.g., orthophosphoric acid.

Conversely, compounds of Formula I can be liberated from the acidaddition salts thereof by treatment with strong bases, e.g., sodium orpotassium hydroxide, sodium or potassium carbonate, or from the metallicand ammonium salts thereof by treatment with acids, especially mineralacids, e.g., hydrochloric or sulfuric acid.

When the compounds of Formula I contain a center of asymmetry, they areordinarily produced in their racemic form. When they exhibit two centersof asymmetry, they are generally obtained in the synthesis as mixturesof two racemates, from which the individual racemates can be isolated ina conventional manner, for example by repeated recrystallization fromsuitable solvents, and can thus be obtained in the pure form.

The racemates can be separated into their optical antipodes inaccordance with a large number of known methods. Thus, it is possible toprecipitate some racemic mixtures as eutectics instead of in the form ofmixed crystals and separate the optical isomers in this manner. Althoughselective precipitation is also possible, chemical separation ispreferred. According to this method, diastereomers are formed from theracemic mixture by reaction with an optically active auxiliary agent.Thus, an optically active acid can optionally be reacted with the aminogroup of a compound of Formula I. For example, diastereomeric salts ofcompounds of Formula I can be formed with an optically active acid,e.g., and tartaric acid, dibenzoyl-( and -()-tartaric acid,diacetyl-(+)- and -()-tartaric acid, camphoric acid, p-camphorsulfonicacid, (I)- and (-)-mandelic acid, and (-)-dinitrodiphenic acid and/orand ()-lactic acid. The desired enantiomer of Formula I is then obtainedby separating the optically active auxiliary agent in accordance withknown methods.

The hydroxy compounds of Formula I (R =OH and/ or R =H) can furthermorebe converted into suitable diastereomeric esters by esterification withone of the above-mentioned optically active acids, which esters can beseparated due to their differing properties. The optically activecompounds of Formula I are in each case obtained by saponification ofthe pure diastereomer. However, it is also possible to prepare theacidic phthalic acid or succinic acid esters, e.g., by reactionrespectively, with phthalic and/ or succinic anhydride, and convert thethusproduced dibasic acids into their diastereomeric salts, by reactionwith an optically active base, e.g., quinine, cinchonidine, brucine,cinchonine, hydroxyhydrindarnine, morphine, l-phenylethylamine,l-uaphthylethylamine, phenyloxynaphthylmethylamine, quinidine and/orstrychnine, from which the pure enantiomers can be obtained.

Especially advantageous is the separation of the racemates or racematemixtures by chromatography employing optically active substratematerials, such as, for example, tartaric acid, starch, cane sugar,cellulose, or cellulose acetate, and optically inactive and/or opticallyactive eluents, for purposes of separation into the pure enantiomers, oran optically inactive substrate material, e.g., silica gel or aluminumoxide, in combination with an optically active eluent. The opticalantipodes can also be separated biochemically by a selective enzymaticreaction. For example, using a hydrolase and racemic ester, one of theenantiomers is selectively saponified and the other remains unchanged,which permits their separation because of their different properties.

Furthermore, it is, of course, possible to obtain optically activecompounds in accordance with the above-described methods by usingstarting substances which are already optically active.

The novel compounds can be employed in a mixture with solid, liquid and/or semiliquid excipients as drugs in the human or veterinary medicine.Suitable vehicles are those organic or inorganic substances which aresuitable for parenteral, enteral, or topical application and which donot react with the novel compounds, such as, for example, water,vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, lactose,amylose, magnesium stearate, talc, Vaseline, cholesterol. Especiallysuitable for parenteral application are solutions, preferably oily oraqueous solutions, as well as suspensions, emulsions, or implants.Suitable for enteral application are tablets, drages, syrups, elixirs,or suppositories, and for topical use, salves, creams, or powders. Theabove-mentioned preparations can be optionally sterilized or mixed withauxiliary agents, such as lubricants, preservatives, stabilizers, orwetting agents, emulsifiers, salts for influencing the osmotic pressure,buffers, coloring, flavoring and/or aromatic substances.

The substances are preferably administered in a dosage of 0.12,000 mg.per dosage unit.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the following examples, the temperatures are set forth in degreescentigrade.

EXAMPLE 1 (a) 3.6 g. of 2-[3-chloro-4-(3-hydroxypiperidino)-phenyl]-allyl alcohol (obtainable from 2-(3-nitro-4- chlorophenyl)-allylalcohol and 3-hydroxypiperidine, catalytic reduction to the aminocompound, diazotization, and exchange of the diazonium group againstchlorine) is hydrogenated in a mixture of methanol and ethyl acetatewith hydrogen at room temperature in the presence of 0.6 g. of a Pd-Ccatalyst (5% by weight Pd). After the absorption of hydrogen isterminated, the reaction mixture is filtered, the filtrate isconcentrated by evaporation, and the residue is fractionated, thusobtaining 2-[3-chloro- 4-(3-hydroxypiperidino)-phenyl]-propanol-(1) as amixture of two racemates; B.P. l80/0.05 mm.; M.P. 7582.

Analogously, by hydrogenation in the presence of Pd-C, from thefollowing starting compounds:

2- 3-chloro-4- 3-hydroxypyrrolidino -phenyl] -allyl alcohol 2-3-bromo-4- 3-hydroxypyrrolidino) -phenyl] -allyl alcohol 2-[3-methyl-4-(3-hydroxypyrrolidino)-phenyl] -allyl alcohol 2- 3-bromo-4-(3-hydroxypiperidino -phenyl] -a1lyl alcohol 2- [3-methyl-4-3-hydroxypiperidino) -phenyl] -allyl alcohol the following compounds areproduced:

2- [3-chloro-4-(3-hydroxypyrrolidino)-phenyl]-1-propanol, B.P.186192/0.01 mm.;

2- 3-bromo-4- 3-hydroxypyrrolidino phenyl] 1- propanol;

2- 3-methyl-4-(3-hydroxypyrrolidino) -phenyl]-1- propanol;

2- [3-bromo-4- 3-hydroxypiperidino) -phenyl]-1-propanol;

2- 3-methyl-4- 3 -hydroxypiperidino) -phenyl] -1-propanol.

(b) 5.4 g. of 2-[3-chloro-4-(3-hydroxypiperidino)- phenyl]-l-propanol(M.P. 7582) is dissolved in 60 m1. of dimethylformamide; under agitationand nitrogen, 1 g. of NaH is added thereto, and the reaction mixture isstirred for 2 hours at 40. Then, 6.2 g. of methyl iodide is graduallyadded dropwise, dissolved in 10 m1. of dimethylformamide. The mixture isagitated at 5060; after 5 hours, another 3.1 g. of methyl iodide in ml.of dimethylformamide is added, and the mixture stirred for another 13hours at 5060. The reaction solution is poured into water, extractedwith ether, the ether phase washed with water, dried over Na SO theether distilled oif, and, after purifying the residue by chromatography(silica gel/ benzene), one obtains2-[3-chloro-4-(3-methoxypiperidino)-phenyl]-1-methoxypropane, B.P.143-146/ 0.1 mm.

Analogously, by reacting2-[3-chloro-4-(3-hydroxypiperidino)-phenyl]-1-propanol with NaH andethyl, npropyl, isopropyl, n-butyl, isobutyl, or sec.-butyl iodide, thefollowing compounds are produced:

2- 3-chloro-4-(3ethoxypiperidino) -phenyl] -1-ethoxypropane 2-[3-chloro-4-(B-n-propoxypiperidino) -phenyl] -1-npropoxypropane2-[3-chloro-4-(3-isopropoxypiperidino)-pheny1]-1-isopropoxypropane 2-3-chloro-4- (3-n-butoxypiperidino -phenyl] -1-nbutoxypropane 23-chloro-4- 3-isobutoxypiperidino -phenyl] -1-isobutoxypropane 2- [3-chloro-4- 3-sec.-butoxypiperidino -phenyl] -1-sec.-

butoxypropane In place of the above-mentioned alkyl iodides, it isalsopossible to use the corresponding bromides or sulfates.

(c) 5.4 g. of 2-[3-chloro-4-(3-hydroxypiperidino)- phenyl]-propanol(M.P. 7582) is dissolved in 25 ml. of pyridine. Then, 25 ml. of aceticanhydride is added thereto, the reaction mixture is allowed to stand for24 hours at room temperature, poured into H O, extracted with ether,washed with a NaI-ICO solution and water, dried over Na SO the solventis distilled 'off, and the residue is fractionated, thus obtaining2-[3-chloro-4-(3-acetoxypiperidino)phenyl]-1-propyl acetate as mixtureof two racemates having the boiling point of 175178/ 0.05 mm.

Analogously from the higher melting racemate of 2-[3-chloro-4-(3-hydroxypiperidino) phenyl] 1 propanol (M.P. 83-85), adiacetate is obtained having the boiling point of 175-177/ 0.05 mm., andfrom the lower-melting racemate (M.P. 7072) a diacetate having theboiling point of 175-180/0.05 mm.

14 EXAMPLE 2 A solution of 5.3 g. of2-[3-chloro-4-(3-hydroxypiperidino)-phenyl]-propanol (produced from2-[3-chloro-4- (3-hydroxypiperidino)-phenyl]-propionitrile byhydrogenation in a pyridine-H O-acetic acid mixture in the presence ofRaney nickel and sodium hypophosphite) in 20 ml. of ether is addeddropwise to a suspension of 1.0 g. of LiAlH in 50 ml. 'of ether. Thereaction mixture is refluxed for 2 hours, whereafter'2 ml. of ethylacetate and then 20 ml. of an aqueous NH Cl solution are added thereto.The ether phase is separated, washed with H O, dried over Na SO thesolvent is distilled off, and in this way, 2 [3chloro-4-(3-hydroxypiperidino)-phenyl]-1- propanol is produced as amixture of two racemates; M.P. 75-82" (from ethyl acetate/hexane).

EXAMPLE 3 (a) 6.2 g. of the ethyl ester of2-[3-chloro-4-(3-hydroxypiperidino)-phenyl]-propionic acid (mixture oftwo racemates, M.P. -165) is refluxed in 300 ml. of dry tetrahydrofuranwith 1.0 g. of LiAlH After cooling, any excess LiAlH, is decomposed withmoist tetrahydrofuran; 6 ml. of aqueous 1 N NaOH is added dropwise, themixture is filtered, the solvent is distilled off, the residue is takenup in ether, washed with water, dried over Na SO the solvent distilledolf, and one obtains thereby 2-[3-chloro-4-(3-hydroxypiperidino)-phenyl]-1-propanol as a mixture of tworacemates, M.P. 7582.

The same product is analogously producible from other esters of 2-3-chloro-4- 3-hydroxypiperidino -phenyl] propionic acid or from the freeacid itself.

(b) 5.4 g. of 2 [3 chloro-4-(3-hydroxypiperidino)- phenyl]-propanol isdissolved in 25 ml. of pyridine; under ice cooling, 5.6 g. of hexanoylchloride is added dropwise to the reaction mixture, and the latter isallowed to stand for 18 hours at room temperature and then poured intowater, extracted with ether, and the ether phase washed with aqueousNaHCO solution and H 0. After drying over Na SO the ether is distilledoff, and after purification by chromatography (silica gel/benzene),2-[3-chloro- 4- 3-hexanoyloxypiperidino) -phenyl]-1-propyl hexanoate isobtained, B.P. 210215/0.05 mm.

Analogously, by reaction with acetyl chloride pripionyl chloride butyrylchloride pentanoyl chloride or benzoyl chloride,

in pyridine, the following compounds are obtained:

2-[3-chloro-4-(3-acetoxypiperidino)-pheny1] 1 propyl acetate, B.P.178/0.05 mm.;

2 [3 chloro-4-(3-propionyloxypiperidino)-phenyl]1- propyl propion-ate,B.P. -200/ 0.1 mm.;

2 [3 chloro 4-(S-butyryloxypiperidino)-phenyl]-1- propyl butyrate;

2 [3 chloro 4-(3-pentanoyloxypiperidino)-phenyl]-1- propyl pentanoate;

2 [3 chloro 4-(3-benzoyloxypiperidino)-phenyl]-1- propyl benzoate.

EXAMPLE 4 (a) Analogously to Example 3, by reduction with LiAlH thelow-melting racemates of 2-[3-chloro-4-(3-hydroxypiperidino)-phenyl]-1-propanol, M.P. 70-72, is produced from thelow-meling racemate of 2-[3-chloro-4-(3-hydroxypiperidino)-phenyl]-propionic acid (M.P. 140- 143 and/or fromthe corresponding esters.

(b) Analogously to Example 3, by reduction with LiAlH the high-meltingracemate of 2-[3-chloro-4-(3- hydroxypiperidino)-phenyl]-1-propanol,M.P. 83-85", is obtained from the high-melting racemate of 2-[3-chlor'o-4-(3-hydroxypiperidino)-phenyl] propionic acid (M.P. 179-181) and/ orfrom the corresponding esters.

1 EXAMPLE 5 In analogy to Example 3, by reduction with LiAlH and usingthe .following starting compounds:

3 -chloro-4- (3 -hydroxypyrrolidino) -phenylacetic acid 3 -bromo-4- 3-hydroxypyrrolidino -phenylacetic acid 3-methyl-4- 3 -hydroxypyrrolidino-phenylacetic acid 3-chloro-4- 3-hydroxypiperidino) -phenylacetic acid3-bromo-4- 3-hydroxypiperidino) -phenylacetic acid 3-methyl-4-3-hydroxypiperidino -phenylacetic acid 2- 3-chloro-4-3-hydroxypyrrolidino -phenyl] -propionic acid 2- 3 -bromo-4-3-hydroxypyrrolidino -phenyl] -propionic acid 2- [3 -methyl-4- 3-hydroxypyrrolidino -phenyl] -propionic acid 2- 3 -b romo-4- (3-hydroxypiperidino) -phenyl] -propionic acid 2- [3 -m ethyl-4- (3-hydroxypip eridino) -phenyl] -p ropionic acid and/ or the esters ofthese acids, the following compounds are obtained:

2- 3 -chloro-4- 3-hydroxypyrrolidino -phenyl] -eth anol 2- [3-bromo-4-3-hydroxypyrrolidino -phenyl] -ethanol 2- 3-rnethyl-4-3-hydroxypyrrolidino -phenyl] -ethanol 2- [3-chloro-4-3-hydroxypiperidino -phenyl] -ethanol,

M.P. 98-100, B.P. l80182/O.l mm.

2- [3-bromo-4- 3 -hydroxypip eridino -phenyl] -ethanol 2- [3-methy1-4-3-hydroxypiperidino -phenyl] -ethanol 2-[3-chlo1'o-4-(3-hydroxypyrrolidino) -phenyl] -1- propanol, B.P. 186-1920.1 mm.

2- 3-bromo-4- (3-hydroxypyrrolidino -phenyl] -1- propanol,

2- [3-methyl-4- 3-hydroxypyrrolidino -phenyl] 1- propanol 2- 3-bromo-4-(3-hydroxypiperidino -pheny1] 1- propanol 2- 3-methyl-4- (3-hydroxypiperidino -phenyl] 1- propanol.

EXAMPLE 6 4.7 g. of l-bromo-2-[3-chloro-4-(3-hydroxypiperidino)-phenyl]-propane (produced from 4-bromo-3-nitroacetophenone by reactionwith 3-hydroxypiperidine, catalytic hydrogenation of the thus-produced4-(3-hydroxypiperidino)3-nitroacetophenone, diazotization, and Sandmeyerreaction to 3 chloro-4-(3-hydroxypiperidino)-acetophenone [B.P.190195/0.2 mm.], reaction with methylmagnesium iodide to 2[3-chloro-4-(3-hydroxypiperidino)-phenyl1-2-propanol (M.P. 110-112),dehydration by refluxing with p-toluenesulfonic acid in toluene,bromination with N-bromosuccinimide in boiling C01 and subsequentcatalytic hydrogenation) is refluxed for 4 hours in a mixture of 40 ml.of water and 30 ml. of ethanol with 2 g. of KOH. Then, 50 ml. of thesolvent is distilled off, the reaction mixture diluted with 20 ml. ofwater, extracted with ether, the organic phase washed with water, driedover Na SO the ether distilled ofl, and 2[3-chloro-4-(3-hydroxypiperidino)-phenyl] -propanol- (1) is obtained asa mixture of two racemates, B.P. l80/ 0.05 mm.; M.P. 75-82".

EXAMPLE 7 10 g. of 2-(4-amino-3-chlorophenyl)-1-propanol (obtainablefrom 2-(4-amino-3-chlor0phenyl)-propionic acid [M.P. 114-115 byreduction with LiAlH is refluxed with 28 g. of 1,4-dibromobutan-2-ol(B.P. 70-75/0.4 mm.; obtainable from 1,2,4-trihydroxybutane and HBr) for7 hours in 70 ml. of water is added dropwise. Thereafter, the mixture,wherein 2-[3-chloro-4-(4-bromo-3-hydroxy-l-butylamino) -phenyl]-1-propanol and 2-[3-chloro- 4(4-bromo-2-hydroxyl-l-butylamino)-phenyl]-l-propa nol are formed asintermediates, is refluxed for another 3 16 hours; ml. of the solvent isdistilled 01f, the reaction mixture is diluted with 30 ml. of water,extracted with ether, the organic phase washed with Water, dried over NaSO the ether distilled off, and in this manner, 2-[3- chloro4-(3-hydroxypyrrolidino)-phenyl]-l-propanol is obtained as a mixture oftwo racemates, B.P. 186192/ EXAMPLE 8 19 g. of2-[3-amino-4-(3-hydroxypiperidino)-phenyl]- l-propanol (producible from2-[3-amino-4-(3-hydroxypiperidino)-phenyl]-propionic acid by reductionwith LiAlH is dissolved in 75 ml. of H 0 and 26 ml. of concentrated HCl;at 0-5 5.5 g. of NaNO dissolved in 25 ml. of H 0, is added thereto. Thethus-obtained mixture is poured in a thin stream to a slightly boilingsolution of 9 g. of Cu CI in 40 ml. of concentrated HCl, and thenallowed to stand for another 30 minutes at -95. The reaction mixture isthen cooled, saturated with H 8, filtered, and Na CO is stirred into themixture until an alkaline reaction is attained. Thereafter, the mixtureis extracted with ether, the ether phase washed with H O, dried over NaSO filtered, the ether distilled OE, and the product thus obtained is2-[3-chloro-4-(3-hydroxypiperidino) phenyl]-propanol-( 1) as a mixtureof two racemates, B.P. 180/0.05 111111.; M.P. 75-82".

EXAMPLE 9 Analogously to Example 3, from2-[3-chloro-4-(3-oxopiperidino)-phenyl]-1-propanol (obtainable byreacting 2- (3 nitro-4-bromophenyl)-l-propanol with 3-piperidoneethylene ketal, reduction of the thus-produced 2-[3-nitro-4-(3,3-ethylenedioxypiperidino)-phenyl] -1-propanol to the aminocompound, diazotization under simultaneous ketal hydrolysis, andSandmeyer reaction) the compound 2-[3- chloro4-(3-hydroxypiperidino)-phenyl]-propanol-(1) is obtained as a mixture oftwo racemates, B.P. l80/ 0.05 mm.; M.P. 75-82".

EXAMPLE 10 8.0 g. of 2-[3-chloro-4-(3-bromopiperidino)-phenyl]-l-propanol (obtainable from 2-(3-nitro-4-bromophenyl)- l-propanol byreaction with 3,4-dehydropiperidine, reduction of the thus-produced2-[3-nitro-4-(3,4-dehydropiperidino)-phenyl]-1propanol, Sandmeyerreaction, bromination of the thus-obtained2-[3-chloro-4-(3,4-dehydropiperidino)-phenyl]-l-propanol withN-bromosuccinimide, and subsequent catalytic hydrogenation) is refluxedfor 6 hours in a mixture of 80 ml. of water and 40 m1. of ethanol with 4g. of KOH. After cooling, 80 ml. of concentrated aqueous NaCl solutionis added thereto, the mixture extracted with ether, the ether phasewashed with water, dried over Na SO and the solvent ditsilled ofI', thusobtaining 2-[3-chloro-4-(3-hydroxypiperidino)-phenyl]-propanol-(l) as amixture of two racemates, B.P. 180/0.05 mm.; M.P. 75-82.

EXAMPLE 11 4.6 g. of 1-propionyloxy-2-[3-chloro-4-(5-propionyloxy-3,4dehydropiperidino)-phenyl] -propane (obtainable from 2[3-ch1oro-4(5-bromo-3,4-dehydropiperidino)-phenyl]- l-propanol byreaction with sodium propionate and propionic acid in the presence of asmall amount of propionic anhydride) is dissolved in a mixture of 40 ml.of methanol and 20 ml. of ethyl acetate and hydrogenated at roomtemperature in the presence of 1 g. of a Pd-C catalyst (5% by WeightPd). After the hydrogen absorption is terminated, the mixture isfiltered, the filtrate evaporated, and the residue is fractionated, thusobtaining 2-[3-chloro 4(3-propionyloxypiperidino)-phenyl]-l-propionyloxypropane as a mixture oftwo racemates, B.P. 200/0.1 mm.

1 7 The following examples include pharmaceutical compositions ofthe-novel compounds which can be produced according to conventionalstandards:

Example A.Tablets The coating is a conventional mixture of corn starch,

sugar, talc, and tragacanth and amounts to 150 mg.

Example C.Solution for injection A solution of 2 kg. of thehydrochloride of 2-[3-chloro- 4 (3 hydroxypiperidino)-phenyl]-1-propanolin 198 kg. of distilled Water is prepared and filled into 2 ml. ampoulesin such a manner that each ampoule contains 20 mg. of saidhydrochloride.

Example D.Syrup A mixture of 2 [3 chloro4-(3-acetoxypiperidino)-phenyl]- l-propyl acetate Glycerol (twicedistilled) 7.5 Cane sugar 56.0 Methyl p-hydroxybenzoate 0.07 n-Propylp-hydroxybenzoate 0.03 Ethanol 10.0 Flavorings As desired is preparedand mixed with distilled water in such a manner that the volume of theentire preparation is 100 l. A dosage unit (5 ml.) contains 20 mg. ofactive substance.

Example E.-Hard gelatin capsules Each hard gelatin capsule is filledwith a fine powder consisting of Mg. 2 [3 chloro4-(3-hydroxypiperidino)-phenyl]- 1 propanol Lactose 180 Talc 18Magnesium stearate 2 Instead of the hydrochloride other physiologicallycompatible acid or base addition salts, respectively, of 2- [3 chloro4-(3-hydroxypiperidino)-phenyl]-1-propanol or 2 [3 chloro 4(3-acetoxypiperidino)-phenyl]-1- propyl acetate or other compoundscovered by Formula 1, as well as the physiologically compatible acidaddition salts, thereof, can be incorporated into similar compositions.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:

1. Compounds of the formula wherein R is OH, alkoxy of up to 6 carbonatoms, cycld alkoxy of up to 6 carbon atoms, aryloxy, aralkoxy of 7- 12carbon atoms, or alkanoyloxy of up to 18 carbon atoms; R is H, alkyl ofup to 6 carbon atoms, cycloalkyl of up to 6 carbon atoms, aryl, aralkylof 7-12 carbon atoms, or alkanoyl of up to 18 carbon atoms; aryl in eachof the above instances is phenyl, tolyl, xylyl or naphthyl; R is H or CHR is Cl, Br or CH and n is 2 or 3; and the physiologically acceptableacid addition and quaternary ammonium salts thereof.

2. A compound of 1 wherein R is OH.

3. A compound of claim 2 wherein n is 3.

4. A compound of claim 1 wherein R is alkanoyloxy of up to 18 carbonatoms.

5. A compound of claim 4 wherein n is 3.

6. A compound of claim 1 wherein R is H.

7. A compound of claim 6 wherein n is 3.

8. A compound of claim 1 wherein R is alkanoyl of up to 18 carbon atoms.

9. A compound of claim 8 wherein n is 3.

10. A compound of claim 1 wherein R is CH 11. A compound of claim 1wherein R is Cl.

12. A compound of claim 1 wherein R is OH, R is CH and n is 3.

13. A compound of claim 1 wherein R is OH, R is H, R is CH and R is Cl.

14. A compound of claim 1 wherein R is alkanoyloxy of up to 18 carbonatoms, R is H, R is CH and R is Cl.

15. A compound of claim 14 wherein n is 3.

16. A compound of claim 1 wherein R is alkanoyloxy and R is alkanoyl,each of up to 18 carbon atoms, R, is CH3 d R4 iS Cl- 17. A compound ofclaim 16 wherein n is 3.

18. A compound of claim 1, 2-[3-chloro-4-(3-hydroxy- 19. A compound ofclaim 1, 1-acetoxy-2-[3-chloro-4- (3 -acetoxypiperidino -phenyl -propane.

20. A compound of claim 1 wherein R is alkanoyloxy of up to 6 carbonatoms.

21. A compound of claim 1 wherein R is alkanoyl of up to 6 carbon atoms.

References Cited UNITED STATES PATENTS 3,641,040 2/ 1972 Carney et al260293.72 3,669,956 6/1972 Borck et al 260239 BF 3,669,972 6/1972 Borcket a1. 260293.73 3,669,973 6/ 1972 Borck et a1. 260--293.73

HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner US. or.X.R.

UMT D STATES PATENT OFFICE CERTEFECATE ()F CGRREQTIQN Dated November 6,1973 Paten t No. 3,770,748

Inventor) Joachlm Borck, et al.

It is certified that error appears in th'e above-identified patent andthat said Letters Patent are hereby corrected as shown below:

IN THE CLAIMS, COLUMN l8:

Claim l8 should read as follows 18. A compound of Claim 1, 2- [3chloro4(3-hydroxy-piperidino)-phenyl]-lpropanol'.

Signed and sealed this 1st day'of Detober 1974.

(SEAL) Attest:

c MARSHALL DANN McCOY M. GIBSON JR" Attesting Officer Commissioner ofPatents USCOMM-DC 60376-P69 A U45. GOVERNMENT PRINTING OFFICE: I968O-rSSB-SZM.

FORM PC4050 (IO-69)

